NO20220050A1 - Neuroendocrine tumor treatment - Google Patents

Description

The present invention relates to organic compounds, more specifically the use of mTOR inhibitors in neuroendocrine tumor treatment.

An mTOR inhibitor as used herein is a compound that targets intracellular mTOR ("mammalian target of rapamycin"). mTOR is a family member of phosphatidylinositol 3-kinase (P13-kinase) related kinase. The compound rapamycin and other mTOR inhibitors inhibit mTOR activity via a complex with its intracellular receptor FKBP12 (FK506-binding protein 12). mTOR modulates translation of specific mRNAs via the regulation of the phosphorylation state of several different translation proteins, mainly 4E-PB1, P70S6K (p70S6 kinase 1) and eEF2.

Rapamycin is a known macrolide antibiotic produced by Streptomyces hygroscopicus with formula

Other mTOR inhibitors include rapamycin derivatives, for example, which include rapamycin substituted at position 40 and/or 16 and/or 32.

Examples of other mTOR inhibitors include 40-O-alkyl-rapamycin derivatives, e.g.

40-O-hydroxyalkyl-rapamycin derivatives, for example 40-O-(2-hydroxy)-ethylrapamycin (everolimus),

rapamycin derivatives which are substituted in the 40 position by heterocyclyl, e.g. 40-epi-(tetrazolyl)-rapamycin (also known as ABT578),

32-deoxo-rapamycin derivatives and 32-hydroxy-rapamycin derivatives, such as 32-deoxorapamycin,

16-O-substituted rapamycin derivatives such as 16-pent-2-ynyloxy-32-deoxorapamycin, 16-pent-2-ynyloxy-32(S or R)-dihydro-rapamycin, or 16-pent-2-ynyloxy-32( S or R)-dihydro-40-O-(2-hydroxyethyl)-rapamycin, rapamycin derivatives which are acylated at the oxygen in position 40, e.g. 40-[3-hydroxy-2-(hydroxy-methyl)-2-methylpropanoate]-rapamycin (also known as CCI779 or temsirolimus),

rapamycin derivatives (also sometimes called rapalogs) as disclosed in WO9802441 or WO0114387, such as e.g. include AP23573, such as 40-O-dimethylphosphinylrapamycin,

compounds disclosed under the name biolimus (biolimus A9), which include 40-O-(2-ethoxy)ethyl-rapamycin, and compounds disclosed under the name TAFA-93, AP23464, AP23675, or AP23841; or

mTOR inhibitors such as disclosed in WO2004101583, WO9205179, WO9402136, WO9402385 and WO9613273.

Preferred mTOR inhibitors include

rapamycin, and/or

40-O-(2-hydroxyethyl)-rapamycin, and/or

32-deoxorapamycin, and/or

16-pent-2-ynyloxy-32-deoxorapamycin, and/or

16-pent-2-ynyloxy-32 (S or R)-dihydro-rapamycin, and/or

16-pent-2-ynyloxy-32 (S or R)-dihydro-40-0-(2-hydroxyethyl)-rapamycin, and/or 40-[3-hydroxy-2-(hydroxy-methyl)-2-methylpropanoate ]-rapamycin (also known as CCI779) and/or

40-epi-(tetrazolyl)-rapamycin (also known as ABT578), and/or

the so-called rapalogs, e.g. as disclosed in WO9802441, WO0114387 and WO0364383, AP23573, AP23464, AP23675 or AP23841, e.g. AP23573, and/or compounds disclosed under the name TAFA-93, and/or

compounds identified under the name biolimus.

More desirably, an mTOR inhibitor is selected from the group consisting of rapamycin, and/or

40-O-(2-hydroxyethyl)-rapamycin, and/or

32-deoxorapamycin, and/or

16-pent-2-ynyloxy-32-deoxorapamycin, and/or

16-pent-2-ynyloxy-32 (S or R)-dihydro-rapamycin, and/or

16-pent-2-ynyloxy-32 (S or R)-dihydro-40-0-(2-hydroxyethyl)-rapamycin, and/or 40-[3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate ]-rapamycin (also known as CCI779) and/or

40-epi-(tetrazolyl)-rapamycin (also known as ABT578), and/or

AP23573,

such as 40-O-(2-hydroxyethyl)-rapamycin.

mTOR inhibitors, on the basis of observed activity, have been found to be useful e.g. as immunosuppressants, e.g. in the treatment of acute allograft rejection and also have potent antiproliferative properties that make them useful for cancer chemotherapy, especially for the treatment of solid tumors, especially advanced solid tumors.

Endocrine, e.g. neuroendocrine tumors (NETs), are found in the endocrine system. Carcinoid tumors are a special type of tumor, generally classified as endocrine tumors. Carcinoid tumors belong to the family of neuroendocrine tumors that arise from the neuroendocrine cell system. In the digestive tract, these tumors develop deep in the mucosa, grow slowly and expand into the underlying submucosa and the mucosal surface. This results in the formation of small hard nodules that protrude into the intestinal lumen. Pancreatic neuroendocrine tumors (small eye cell tumors), which were previously classified as APUDomas (tumors of the amine precursor uptake and decarboxylation system), comprise less than half of all neuroendocrine tumors and only 1-2% of all pancreatic tumors. Pancreatic NETs can arise either in the pancreas (insulinomas, glucagonomas, non-functioning pancreatic NETs, pancreatic NETs causing hypercalcemia) or at both pancreatic and extrapancreatic sites (gastrinomas, VIPomas, somatostatinomas, GRFomas). The hormones secreted by pancreatic NETs depend on the cell origin and are physiologically involved in a network of autocrine, paracrine, endocrine and neurotransmitter communication. While hormone secretion is not observed in all cases of pancreatic NET, the apparently "nonfunctioning" (ie, nonsecreting) pancreatic NETs tend to be more aggressive and present with symptoms of tumor size (see, e.g., Barakat et al, Endocrine-related cancer 2004;11:1-18, and Tomassetti et al, Ann Oncol 2001;12 (Suppl 2):S95-S99).

All pancreatic NETs, with the exception of 90% of insulinomas, have long-term metastatic potential. Most are overtly malignant at the time of diagnosis and 60% or more present with liver metastases. The most common cause of death from pancreatic NET is liver failure (Warner RRP, Gastroenterology 2005;128:1668-16842005).

In a recent review, the 5-year survival rate in a series of 83 consecutive patients with pancreatic NETs has been reported to be 55.3%, pointing to an unmet medical need for continued treatment in patients with pancreatic NETs 'is whose disease has developed after one or more rounds of chemotherapy.

Carcinoid tumors have historically been classified, according to their point of origin in embryonic development, as arising from the foregut (eg, bronchial, lung, or gastric carcinoid), in the midgut (eg, small bowel or cecal carcinoid), or hindgut (e.g. rectal carcinoid), see e.g. Kulke M., Cancer Treatment Reviews 2003;29:363-370.

Primary tumors from the early intestine are limited to the thymus, lung, stomach and duodenum. Midgut carcinoids are located in the distal ileum, cecum and near colon. An interesting subset of this group are appendiceal carcinoids, which are often benign and rarely give rise to metastatic disease. Midgut carcinoids dominate the malignant carcinoid tumors, especially when the carcinoid syndrome is present.

Tumors in the hindgut are primarily located in the distant colon and rectum.

Data suggest that the incidence of lung and stomach carcinoid has increased in the last two decades.

According to histological criteria, carcinoids can be divided into typical (TC) and atypical (AC) carcinoids. Carcinoids can be placed in a spectrum of neuroendocrine tumors, ranging from low-grade malignant TC to intermediate AC to high-grade large cell neuroendocrine carcinoma and small cell lung carcinoma.

Carcinoid lung tumors include e.g. neuroendocrine carcinoma, Kulchitsky cell carcinoma (KCC), bronchial carcinoid tumors, bronchial adenomas, typical carcinoids, atypical carcinoids, carcinoid syndrome, small cell carcinomas, Kulchitsky cells, argentaffin cells, lung carcinoids, neuroendocrine lung tumors, (primary) lung neoplasms, bronchopulmonary carcinoid tumors, lung neoplasms, lung cancers, lung cancers, intrabronchial mass.

Bronchial carcinoid tumors can arise from neurosecretory cells in the bronchial mucosa and were previously classified as bronchial adenomas. Bronchial carcinoids are now classified as low-grade malignant neoplasms because of their potential to cause local invasion, their tendency to local recurrence, and their incidental metastases to extra-thoracic sites.

Bronchial carcinoids belong to a group of neuroendocrine tumors that cover a range of tumors from bronchial carcinoid at one end of the spectrum, with a small cell carcinoma, or possibly large cell neuroendocrine tumors at the other end. They show a wide range of clinical and biological behavior and include the potential to synthesize and secrete peptide hormones and neuroamines, particularly adrenocorticotropic hormone (ACTH), serotonin, somatostatin and bradykinin.

Bronchial carcinoid tumors can arise from Kulchitsky cells (argentaffin cells) within the bronchial mucosa. The predominant distribution of cells is thought to occur at the bifurcation of the lobar bronchus. These cells are neurosecretory cells belonging to the amine precursor uptake and decarboxylation (APUD) system. They have the capacity to synthesize serotonin (5-hydroxytryptamine), 5-hydroxytryptophan, ACTH, norepinephrine, bombesin, calcitonin, antidiuretic hormone (ADH) and bradykinin.

Large cell neuroendocrine carcinoma of the lung is a recently recognized clinicopathological entity, which differs from small cell carcinoma and has a poor prognosis.

Typical carcinoid tumors of the lung represent the best differentiated and least biologically aggressive type of lung neuroendocrine tumor. These tumors are characteristically slow growing and tend to rarely metastasize. Atypical carcinoid tumors have a more aggressive histological and clinical picture. They metastasize at a considerably higher rate than typical carcinoid tumors. Carcinoid syndrome has been reported in association with very large bronchopulmonary carcinoid tumors or in the presence of metastatic disease. It is much less common in association with carcinoids of pulmonary origin than those arising within the digestive system. Endocrine syndromes found in association with small cell carcinoma of the lung are found less frequently with carcinoid tumors of the lung; however, some endocrine abnormalities have been attributed to both typical and atypical lung carcinoid tumors.

Carcinoid tumors of the GI system may show an aggressive biology similar to that of adenocarcinomas, especially when located in the colon, stomach and small intestine, see e.g.

Modlin IM et al, Gastroenterology 2005;128:1717-1751. For small bowel carcinoids, which are the most frequent cause of carcinoid syndrome due to metastatic disease in the liver, the incidence of metastasis increases proportionally with the size of the primary tumor (Tomassetti et al 2001, ibidem).

Available incidence and survival data suggest that clinical trials of new anticancer agents in patients with midgut carcinoid tumors may provide the opportunity to investigate an unmet medical need in a growing portion of the carcinoid patient population.

Carcinoid syndrome is caused by hypersecretion of several hormone products by the tumor cells, including kinins, prostaglandins, substance P, gastrin, corticotrophin, and chromogranin A (see, e.g., Davis et al, Gynecology & Obstetrics 1973;137:637-644). Various endocrine or neuroendocrine syndromes may be initial clinical manifestations of either typical or atypical lung carcinoid tumors.

Carcinoid syndrome, hypercortisolism and Cushing syndrome, inappropriate secretion of ADH, increased pigmentation secondary to excess MSH and ectopic insulin production resulting in hypoglycemia are some of the endocrinopathies that can be produced by a pulmonary carcinoid tumor in an otherwise asymptomatic patient.

The most common symptoms are whooping cough, cough, recurrent lung infection, fever, chest discomfort and chest pain, one-sided heavy breathing and shortness of breath, flushing and diarrhoea. Paraneoplastic syndromes are rare and include carcinoid syndrome, Cushing's syndrome, and ectopic growth hormone-releasing hormone secretion.

Other less common symptoms include cardiac manifestations secondary to fibrosis of the endocardium (Jacobsen MB et al, Eur Heart J 1995;16:263-268) which may result in valve regurgitation (valvular heart disease), with varying degrees of heart failure in patients with cardiac manifestations. Dyspnea or asthma-like symptoms, pellagra-like skin lesions with hyperkeratosis, abdominal pain, telangiectasia and paroxysmal hypotension are also seen in a number of patients. Patients with pulmonary carcinoid often show symptoms such as recurrent pneumonia, cough, hemoptysis or chest pain. The majority of lung carcinoid tumors are in the perihilar area. Ectopic secretion of corticotropin from lung carcinoid tumors can also be the cause of Cushing's syndrome. Early in the course, the symptoms are usually episodic and can be triggered by stress, catecholamines and the consumption of food or alcohol. During acute attacks, systolic blood pressure usually falls 20 to 30 mmHg. Endocardial fibrosis can cause valvular heart disease, which usually affects the proximal side of the tricuspid and pulmonary valves and leads to tricuspid insufficiency and secondary right-sided heart failure.

A recent review of chemotherapeutic treatment of carcinoids reports that the sensitivity of these tumors to different cytotoxic drugs is low, and combination does not increase their effectiveness. Based on their review of different combination therapies, which include dacarbazine/fluorouracil or 5-fluorouracil/epirubicin, the authors conclude that they are unable to recommend a specific chemotherapeutic regimen for patients with well-differentiated neuroendocrine malignancies of the GI tract (Arnold R, Rinke A et al, Clinical Gastroenterology 2005;19(4):649-656). The apparent refractoriness of such tumors to currently available therapies points to an unmet medical need for treatment in this patient population.

As part of the endocrine system that regulates hormones, the pituitary gland controls many of the other glands through secretion. Our "master gland", the pituitary gland, makes some hormones, but also acts as an intermediary between the brain and other endocrine glands. Our hormones and the pituitary gland perform many homeostatic and specialized functions, such as bone growth and uterine contractions.

Neurons carry messages regarding the production of hormones between the pituitary gland and the hypothalamus. Both are located at the base of the brain, housed in a rounded part of the bone, carefully protected. They are connected by a bundle of neurons called the infundibulum. Together, they work to regulate all the hormones that circulate in the bloodstream, and control things such as growth and hair pigmentation. Hormones are long-distance messengers that can inform cells when to become active or remain dormant. The pituitary gland controls the thyroid, kidney glands, ovaries and testicles, although it is only the size of a pea.

There are different parts of the pituitary gland that have selective functions. The posterior lobe, called the neurohypophysis, releases the hormones vasopressin and oxytocin, but does not produce them. Vasopressin is an antidiuretic that controls how the kidneys absorb water. Oxytocin is a special hormone that is only present during childbirth to speed up contractions. The anterior lobe of the pituitary gland is called the adenohypophysis. It produces a number of hormones, such as prolactin, which stimulate milk production in women. Melanocyte stimulates the body to produce melanin for skin and hair pigmentation. Follicle-stimulating hormone indicates where and when hair should grow during development. The very important growth hormone controls bone growth to determine height, especially active during adolescence. Hormones control glands as well. The thyroid responds to thyrotropin, the adrenal glands are stimulated by adrenocorticotropin, and the gonads are affected by luteinizing hormone. The pituitary gland is responsible for many steps and aspects of our maturation. Pituitary tumors are generally benign, and comprise only 10% of brain tumors. However, due to the location of the pituitary gland, at the bottom of the skull, a pituitary tumor grows upwards, and eventually many pituitary tumors press against the optic nerves and cause vision problems. Symptoms vary depending on the type of tumor growing and which area of the pituitary gland it affects. Pituitary tumors can cause symptoms caused by excess production of pituitary hormones and symptoms caused by reduced production of pituitary hormones. Other symptoms may be due to the proximity of these tumors to local brain structures, such as the optic nerves that lead to vision loss. Each individual also experiences symptoms differently, and the symptoms may resemble other conditions or medical problems.

The most common type of pituitary tumor is called a clinically non-functioning tumor, because patients do not have the classic pituitary syndromes from excess hormones, such as in acromegaly. These types of tumors can be detected during an evaluation of a random problem. A clinically nonfunctioning tumor can cause hypopituitarism, or an underactive pituitary gland, which can lead to sexual dysfunction, reduced sperm production, and cessation of the woman's menstrual period, along with fatigue.

Another common pituitary tumor is called a prolactinoma, a benign tumor that produces the hormone prolactin. Prolactin stimulates breast milk production after birth. Women with a prolactinoma may have reduced or absent menstrual cycles along with breast milk production.

An unusual pituitary tumor causes excess production of growth hormone (a hormone necessary for normal growth in children) and results in acromegaly. In adults, such tumors lead to excessive somatic growth and several systemic medical consequences. Another unusual pituitary tumor results in Cushing's disease, a disorder that has excessive steroid production.

Multiple endocrine neoplasia type 1 (MEN 1) is a relatively uncommon hereditary disease. Individuals who inherit the gene for MEN 1 have an increased chance of developing overactivity and enlargement of certain endocrine glands. The endocrine glands most often affected by MEN 1 are the parathyroid, pancreas and pituitary glands. Almost everyone who inherits MEN 1 develops overactivity of the parathyroid glands (hyperparathyroidism) at some stage in their lives. The other endocrine glands become overactive less often, however, people who inherit MEN 1 will usually develop overactivity in more than one endocrine gland. Overactivity in different endocrine glands can occur simultaneously or at different times during a person's life. MEN 1 can lead to overactivity and enlargement of the three endocrine glands mentioned above (the endocrine glands that start with the letter "p"). People who inherit the gene for MEN 1 are predisposed to develop an overactivity in hormone production from the parathyroid glands, pituitary gland and pancreas (this is why doctors will measure hormones in the blood to check for overproduction of each specific hormone). Increased hormone production is usually associated with enlargement of these glands. Endocrine gland enlargement and hormone overproduction do not usually occur in all areas of an endocrine gland at the same time. Some parts of overactive endocrine glands grow faster than others, and produce more hormone than other parts of the same gland. The parts of a growing endocrine quickly become "lumpy". These lumps are usually benign. Benign lumps in endocrine glands are known as adenomas.

Adenomas are benign (they are not cancerous) and do not spread to other parts of the body. Adenomas in the pituitary gland (pituitary tumours, nervous system tumours) can lead to nerve damage, growth disturbance and changes in the hormonal balance. Symptoms of pituitary adenomas can vary considerably, mainly depending on whether or not the tumor secretes one or more of a number of hormones. Although the tumor does not produce any hormones, its location at the base of the brain can cause significant symptoms. Symptoms may include, for example, double or blurred vision, loss of peripheral vision, sudden blindness, headache, lightheadedness, loss of consciousness, nausea, weakness, unexplained weight changes, absence of menstruation, erectile dysfunction in men, decreased sexual desire, especially in men, growth of the skull, hands and feet, deep voice, changes in the shape of the face (due to changes in the facial bones), gaps between the teeth, joint pain, increased sweating, pink stretch marks on the stomach, increased hair growth, fat deposits where the neck meets the spine, mood changes or depression, get easily bruising, tremors (rapid or irregular heartbeats), tremors, increased appetite, feeling hot, difficulty falling asleep, anxiety, frequent stomach movements, lump in the front of the throat (enlarged thyroid).

It was found that mTOR inhibitors can be used for the treatment of such special types of tumors.

According to the particular findings, the present invention provides several aspects:

1.1 A method of treating endocrine tumors, comprising administering to an individual in need thereof a therapeutically effective amount of an mTOR inhibitor. 1.2 A method of inhibiting the growth of endocrine tumors, comprising administering to an individual in need thereof a therapeutically effective amount of an mTOR inhibitor.

1.3 A method of inhibiting or controlling endocrine tumors, comprising administering to an individual in need thereof a therapeutically effective amount of an mTOR inhibitor.

1.4 A method for inducing endocrine tumor regression, e.g.

tumor mass reduction, which comprises administering to an individual in need thereof a therapeutically effective amount of an mTOR inhibitor.

1.5 A method of treating endocrine tumor invasiveness or symptoms associated with such tumor growth, comprising administering to an individual in need thereof a therapeutically effective amount of an mTOR inhibitor.

1.6 A method for preventing metastatic spread of endocrine tumors or for preventing or inhibiting growth of micrometastasis, comprising administering to an individual in need thereof a therapeutically effective amount of an mTOR inhibitor.

1.7 A method of treating a disorder associated with endocrine tumors, comprising administering to an individual in need thereof a therapeutically effective amount of an mTOR inhibitor.

1.8 The use of an mTOR inhibitor for the production of a drug for use in any method according to 1.1 to 1.7 above.

1.9 A pharmaceutical composition comprising an mTOR inhibitor together with at least one pharmaceutically acceptable excipient, e.g. suitable carrier and/or diluent, such as e.g. includes fillers, binders, disintegrants, flow aids, lubricants, sugars or sweeteners, flavorings, preservatives, stabilizers, softeners and/or emulsifiers, solvents, salts to regulate osmotic pressure and/or buffers; for use in any method or application of 1.1 to 1.7 above.

Endocrine tumors as indicated here include e.g. neuroendocrine tumors, such as include carcinoid tumors, pancreatic neuroendocrine tumors, and tumors of the parathyroid, pancreas, and pituitary glands.

Carcinoid tumors as indicated here include e.g. common and uncommon carcinoids, ranging from low-grade malignant common to intermediate uncommon to high-grade large cell neuroendocrine carcinoma and small cell lung carcinoma; like for example. includes carcinoids arising from

- the foregut, e.g. bronchial, lung or stomach carcinoids, such as

e.g. includes primary tumors of the foregut limited to the thymus, lung, stomach, and duodenum; e.g. carcinoid tumors of the GI system, e.g. located in the colon, stomach or small intestine, e.g. small bowel carcinoids, e.g. which includes

- middle intestine, e.g. small bowel or appendix carcinoids, e.g. located in the distal ileum, cecum and proximal colon, or

- hind gut, e.g. rectal carcinoids.

Carcinoid lung tumors as indicated here include e.g. neuroendocrine carcinoma, Kulchitsky cell carcinoma (KCC) (Kulchitsky cells, argentaffin cells), bronchial carcinoid tumors, bronchial adenomas, e.g. which includes bronchial adenomas such as a small cell carcinoma and large cell neuroendocrine tumors, common carcinoids or unusual carcinoids associated with large bronchopulmonary carcinoid tumors or small cell carcinomas, lung carcinoids, neuroendocrine lung tumors, large cell neuroendocrine carcinoma of the lung, (primary) lung neoplasm, bronchopulmonary carcinoid tumors, lung neoplasm, lung cancer, lung cancer , intrabronchial mass.

Pancreatic neuroendocrine tumors as indicated here include e.g. small eye cell tumours, APUDomas, insulinomas, glucagonomas, non-functioning pancreatic NETs, pancreatic NETs associated with hypercalcaemia, gastrinomas, VIPomas, somatostatinomas, GRFomas.

Endocrine or neuroendocrine tumor symptoms as indicated here include e.g. coughing up blood, coughing, recurrent lung infection, fever, chest discomfort and chest pain, unilateral wheezing, shortness of breath, flushing and diarrhoea, endocrine or neuroendocrine syndromes carcinoid syndrome, such as include manifestation of either common or uncommon pulmonary carcinoid tumors, Cushing's syndrome, inappropriate secretion of ADH, increased pigmentation secondary to excess MSH, and ectopic insulin production resulting in hypoglycemia, ectopic growth hormone-releasing hormone secretion, ectopic secretion of corticotropin, cardiac manifestations secondary to fibrosis of the endocardium (endocardial fibrosis ), valvular regurgitation (valvular heart disease), tricuspid insufficiency, secondary right-sided heart failure, wheezing or asthma-like symptoms, pellagra-like skin lesions with hyperkeratosis, abdominal pain, telangiectasia and paroxysmal hypotension, recurrent pneumonia, cough, chest pain.

Tumors in the parathyroid, pancreas and pituitary glands as indicated here include e.g. pituitary tumors, nervous system tumor, such as adenomas, multiple endocrine neoplasia type 1 (MEN 1).

Pituitary tumor symptoms as indicated here include symptoms associated with excess production of pituitary hormones and symptoms caused by reduced production of pituitary hormones, loss of vision, clinically non-functioning tumor, e.g. associated with hypopituitarism (underactive pituitary gland), e.g. associated with failure of sexual function, reduced sperm production and cessation of the woman's menstrual period, together with exhaustion, prolactinoma, a benign tumor that produces the prolactin hormone, acromegaly, e.g. associated with excess somatic growth hormone and multiple systemic medical consequences, Cushing's disease, nerve damage, growth disturbance, changes in hormone balance, double or blurred vision, loss of peripheral vision, sudden blindness, headache, lightheadedness, loss of consciousness, nausea, weakness, unexplained weight changes , absence of menstruation, erectile dysfunction in men, decreased sexual desire, especially in men, growth of skull, hands and feet, deeper voice, changes in facial shape (due to changes in facial bones), larger spaces between teeth, joint pain, increased sweating, pink stretch marks on the abdomen, increased hair growth, fat deposits where the neck meets the spine, mood swings or depression, bruising easily, tremors (rapid or irregular heartbeats), tremors, increased appetite, feeling hot, difficulty falling asleep, anxiety, frequent stomach movements, lump in the front of the neck (enlarged thyroid).

Where previously and hereinafter a tumor, a tumor disease, a carcinoma or a cancer is mentioned, metastases in the original organ or tissue and/or in any other location are also covered alternatively or in addition, regardless of the location of the tumor and/or the metastasis has.

Disorders associated with endocrine tumors include endocrine or neuroendocrine tumor symptoms and pituitary tumor symptoms, as indicated above. Disorders include diseases.

An mTOR inhibitor can be used, e.g. in any method from 1.1 to 1.8 as described here alone or in combination with one or more, at least one, other medicinal substance.

In other aspects, the present invention provides

2.1 A combination of an mTOR inhibitor with at least one other medicinal substance, e.g. for any application as indicated under 1.1 to 1.8 above.

2.2 A pharmaceutical combination comprising an mTOR inhibitor in combination with at least one other drug substance, e.g. for any application as indicated under 1.1 to 1.8 above.

2.3 A pharmaceutical composition comprising an mTOR inhibitor in combination with at least one other drug substance and one or more pharmaceutically acceptable excipients, e.g. for any application as indicated under 1.1 to 1.8 above.

2.4 The use of an mTOR inhibitor for the production of a drug for use in combination with a second drug substance, e.g. for any application as indicated under 1.1 to 1.8 above.

2.5 Any method in 1.1 to 1.8 above which comprises co-administration, simultaneously or sequentially, of a therapeutically effective amount of an mTOR inhibitor and at least one second drug substance, e.g. in the form of a pharmaceutical combination or composition.

2.6 An mTOR inhibitor in combination with at least one other drug substance for use in the preparation of a drug, e.g. for use in any method in 1.1 to 1.8 above.

2.7 Any method as indicated under 2.1 to 2.6 above, where the mTOR inhibitor is administered periodically.

Combinations include fixed combinations, where an mTOR inhibitor and at least one other drug substance are in the same formulation; kit, where an mTOR inhibitor and at least one second drug substance in separate formulations are provided in the same package, e.g. with instructions for simultaneous administration; and free combinations where an mTOR inhibitor and at least one other drug substance are packaged separately, but instructions for simultaneous or sequential administration are given.

In another aspect, the present invention provides

2.8 A pharmaceutical package comprising a first drug substance that is an mTOR inhibitor and at least one second drug substance, in addition to instructions for combined administration;

2.9 A pharmaceutical package comprising an mTOR inhibitor in addition to instructions for combined administration with at least one other drug substance;

2.10 A pharmaceutical package comprising at least one second drug substance in addition to instructions for combined administration with an mTOR inhibitor;

e.g. for use in any method in 1.1 to 1.8 above.

Treatment with combinations according to the present invention may provide improvements compared to single treatment.

In another aspect, the present invention provides

2.11 A pharmaceutical combination comprising an amount of an mTOR inhibitor and an amount of a second drug substance, the amount being appropriate to produce a synergistic therapeutic effect.

2.12 A method of improving the therapeutic use of an mTOR inhibitor comprising co-administration, e.g. simultaneously or in sequence, of a therapeutically effective amount of an mTOR inhibitor and a second drug substance.

2.13 A method for improving the therapeutic use of a second drug substance comprising simultaneous administration, e.g. simultaneously or in sequence, of a therapeutically effective amount of an mTOR inhibitor and a second drug substance;

e.g. for use in any method in 1.1 to 1.8 above.

In a method in 2.11 to 2.13 above, the activity of an mTOR inhibitor or another drug substance can be enhanced compared to simple treatment, e.g. then combined treatment may result in synergistic effects or they may overcome resistance to an mTOR inhibitor or a chemotherapeutic agent, e.g. when they are used in any method according to 1.1 to 1.8 as described above.

A (pharmaceutical) combination, e.g. composition as indicated under 2.1 to 2.13, includes

a) a first agent which is an mTOR inhibitor and

b) a second drug substance which is a co-agent which is a chemotherapeutic agent, e.g. as defined hereinafter or heretofore.

Treatment of disorders (diseases) according to the present invention includes prophylaxis (prevention).

For such treatment, the appropriate dose will of course vary, depending, for example, on the chemical nature and pharmacokinetic data of a compound used, the individual host, the mode of administration, and the nature and severity of the conditions being treated. However, in general, to obtain satisfactory results in larger mammals, such as humans, an indicated daily dose includes a range

- from about 0.0001 g to about 1.5 g, such as 0.001 g to 1.5 g;

- from about 0.001 mg/kg body weight to about 20 mg/kg body weight, such as 0.01 mg/kg body weight to 20 mg/kg body weight,

for example, administered in divided doses up to four times per day.

In a method, for use or in a combination, pharmaceutical combination or pharmaceutical composition provided by the present invention, an mTOR inhibitor, such as rapamycin or rapamycin derivative, may be administered as appropriate, e.g. at doses known for mTOR inhibitors, by any route of administration, e.g. enterally, e.g. orally, or parenterally. For example, everolimus can be administered, e.g. orally, in doses from 0.1 mg up to 15 mg, such as 0.1 mg to 10 mg, e.g. 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1 mg, 2.5 mg, 5 mg or 10 mg, more desirably from 0.5 mg to 10 mg, e.g. in the form of (dissolving) tablets; e.g. comprising everolimus in the form of a solid dispersion; e.g. a weekly dose may include up to 70 mg, eg 10 to 70, such as 30 to 50 mg, depending on the disease to be treated. Rapamycin or, for example, temsirolimus can be administered parenterally in similar dose ranges.

A second drug substance may be administered in combination therapy as appropriate, e.g. according to a method which is conventional, e.g. analogous to administration indications given for a specific drug for ease of treatment.

A second drug substance according to the present invention can be administered via any conventional route, for example enterally, as e.g. includes nasal, buccal, rectal, oral administration; parenterally, e.g. which include intravenous, intraarterial, intramuscular, intracardiac, subcutaneous, intraosseous infusion, transdermal (diffusion through the intact skin), transmucosal (diffusion through a mucosal membrane), inhalation administration; topical; like for example. includes epicutaneous, intranasal, intratracheal administration; intraperitoneal (infusion or injection into the peritoneal cavity); epidural (epidural) (injection or infusion into the epidural space); intrathecal (injection or infusion into the cerebrospinal fluid); intravitreal (administration via the eye); or via medical devices, e.g. for local delivery, e.g. stents; e.g. in the form of coated or uncoated tablets, capsules, (injectable) solutions, infusion solutions, solid solutions, suspensions, dispersions, solid dispersions; e.g. in the form of ampoules, tubes, in the form of creams, gels, pastes, inhalation powders, foams, tinctures, lipsticks, drops, sprays, or in the form of suppositories.

A second drug substance according to the present invention can be administered in the form of a pharmaceutically acceptable salt or in free form; optionally in the form of a solvent. Pharmaceutical compositions according to the present invention can be produced according to, e.g. analogue, a procedure which is conventional, e.g. by mixing, grinding, coating, dissolving or freeze-drying. Unit dosage forms can contain, for example, from about 0.1 mg to about 1500 mg, such as 1 mg to about 1000 mg.

Pharmaceutical compositions comprising a combination of the present invention and pharmaceutical compositions comprising a second drug substance as described herein may be provided as appropriate, e.g. according to, e.g. analogously, a method as conventional, or as described here for a pharmaceutical composition in the present invention.

The term "second drug substance" as used here means either an mTOR inhibitor different from the first drug substance or a chemotherapeutic agent different from an mTOR inhibitor, preferably any chemotherapeutic agent different from an mTOR inhibitor. For example, a second drug substance as used here includes e.g.

- an anti-cancer drug, preferably an anti-endocrine tumor drug,

- an anti-inflammatory and/or immunomodulatory and/or anti-allergic drug,

- a combination of an anti-cancer drug with an anti-inflammatory and/or immunomodulatory drug and/or anti-allergic drug.

A second drug substance also includes agents useful in the treatment of symptoms associated with carcinoid tumors, such as carcinoid-associated diarrhea (eg, cyproheptadine), carcinoid-associated wheezing (eg, bronchodilators), carcinoid-associated heart failure (eg, diuretics, serotonin inhibitors).

In another aspect, the present invention provides

3. Any method, combination, pharmaceutical combination, pharmaceutical composition or use as indicated under 1.1 to 1.9 and 2.1 to 2.13 above wherein an mTOR inhibitor is selected from rapamycin or a rapamycin derivative, such as

rapamycin, and/or

40-O-(2-hydroxyethyl)-rapamycin (also known as everolimus), and/or 32-deoxorapamycin, and/or

16-pent-2-ynyloxy-32-deoxorapamycin, and/or

16-pent-2-ynyloxy-32 (S or R)-dihydro-rapamycin, and/or 16-pent-2-ynyloxy-32 (S or R)-dihydro-40-0-(2-hydroxyethyl)-rapamycin , and or

40-[3-hydroxy-2-(hydroxy-methyl)-2-methylpropanoate]-rapamycin (also known as CCI779) and/or

40-epi-(tetrazolyl)-rapamycin (also known as ABT578), and/or the so-called rapalogs, such as e.g. disclosed in WO9802441, WO0114387 and WO0364383, AP23573, AP23464, AP23675 or AP23841, e.g.

AP23573, and/or

compounds disclosed under the name TAFA-93, and/or compounds disclosed under the name biolimus;

e.g. 40-O-(2-hydroxyethyl)-rapamycin (here also referred to as "compound A").

In a preferred aspect, the present invention provides any method, combination, pharmaceutical combination, pharmaceutical composition or use as indicated under 1.1 to 1.9 and 2.1 to 2.13 above for treating neuroendocrine tumors.

In another preferred aspect, the present invention provides any method, combination, pharmaceutical combination, pharmaceutical composition or use as indicated under 1.1 to 1.9 and 2.1 to 2.13 above for treating carcinoid tumors.

In another preferred aspect, the present invention provides any method, combination, pharmaceutical combination, pharmaceutical composition or use as indicated under 1.1 to 1.9 and 2.1 to 2.13 above for treating pituitary tumors.

Anticancer drugs that are likely to be useful as a combination partner with an mTOR inhibitor, e.g. likely to be useful according to the present invention include, for example

i. a steroid; e.g. prednisone.

ii. an adenokinase inhibitor; that target, reduce or inhibit nucleobase, nucleoside, nucleotide and nucleic acid metabolism, such as 5-lodotubercidin, which is also known as 7H-pyrrolo[2,3-d]pyrimidin-4-amine, 5-iodo-7-β-D -ribofuranosyl-(9Cl).

iii. an adjuvant; which enhances 5-FU-TS binding as well as a compound which targets, reduces or inhibits alkaline phosphatase, such as leucovorin, levamisole.

iv. an adrenal cortex antagonist; which target, reduce or inhibit the activity of the adrenal cortex and alter the peripheral metabolism of corticosteroids, resulting in a decrease in 17-hydroxycorticosteroids, such as mitotane.

v. an AKT reaction pathway inhibitor; such as a compound that targets, reduces or inhibits Akt, also known as protein kinase B (PKB), such as deguelin, which is also known as 3H-bis[1]benzopyrano[3,4-b:6',5' -e]pyran7(7aH)-one, 13,13a-dihydro-9,10-dimethoxy-3,3-dimethyl-, (7aS, 13aS)-(9Cl); and triciribine, which is also known as 1,4,5,6,8-pentaazacenaphtylen-3-amine, 1,5-dihydro-5-methyl-1-β-D-ribofuranosyl-(9Cl).

we. an alkylating agent; which cause alkylation of DNA and which result in breaks in the DNA molecules as well as cross-linking of twin strands, thus interfering with DNA replication and transcription of RNA, such as chlorambucil, cyclophosphamide, dacarbazine, lomustine, procarbazine, e.g. in the form of a hydrochloride, thiotepa, melphalan, temozolomide (TEMODAR®), carmustine, ifosfamide, mitomycin, altretamine, busulfan, macloretamine hydrochloride, nitrosourea (BCNU or Gliadel), streptozocin, estramustine. Cyclophosphamide can be administered e.g. in the form in which it is sold, e.g. under the trademark CYCLOSTIN®; and ifosfamide as HOLOXAN®. vii. an angiogenesis inhibitor; that target, reduce or inhibit the production of new blood vessels, e.g. which target methionine aminopeptidase-2 (MetAP-2), macrophage inflammatory protein-1 (MIP-1alpha), CCL5, TGF-beta, lipoxygenase, cyclooxygenase and topoisomerase, or which indirectly target p21, p53, CDK2 and collagen synthesis, such as e.g. includes fumagillin, which is known as 2,4,6,8-decatetraenedioic acid, mono[(3R,4S,5S,6R)-5-methoxy-4-[(2R,3R)-2-methyl-3-(3 -methyl-2-butenyl)oxiranyl]-1-oxaspiro[2.5]oct-6-yl] ester, (2E,4E,6E,8E)-(9CI); shikonin, which is also known as 1,4-naphthalenedione, 5,8-dihydroxy-2-[(1R)-1-hydroxy-4-methyl-3-pentenyl]-(9Cl); tranilast, which is also known as benzoic acid, 2-[[3-(3,4-dimethoxyphenyl)-1-oxo-2-propenyl]amino]-(9Cl); ursolic acid; suramin; bengamide or a derivative thereof, thalidomide, TNP-470. viii. an anti-androgen; that block the action of androgens of adrenal or testicular origin that stimulate the growth of normal or malignant prostate tissue, such as nilutamide; bicalutamide (CASODEX®), which can be formulated e.g. as disclosed in US4636505.

ix. an anti-estrogen; which antagonize the effect of estrogens on the estrogen receptor level, such as e.g. includes an aromatase inhibitor, which inhibits estrogen production, i.e. the conversion of the substrates androstenedione and testosterone into estrone and estradiol respectively, such as e.g. includes atamestane, exemestane, formestane, aminoglutethimide, rogletimide, pyridoglutethimide, trilostane, testolactone, ketoconazole, vorozole, fadrozole, anastrozole, letrozole, toremifene; bicalutamide; flutamide; tamoxifen, tamoxifen citrate; tamoxifen; fulvestrant; raloxifene, raloxifene hydrochloride. Tamoxifen can e.g. administered in the form in which it is sold, e.g. NOLVADEX®; and raloxifene hydrochloride is marketed as EVISTA®. Fulvestrant can be formulated as described in US4659516 and marketed as FASLODEX®. x. an anti-hypercalcemic agent; which are used to treat hypercalcemia, such as gallium (III) nitrate hydrate; and pamidronate disodium.

xi. an antimetabolite; that inhibit or destroy the synthesis of DNA resulting in cell death, such as 6-mercaptopurine; cytarabine; fludarabine; flexuridine; fluorouracil; 5-fluorouracil (5-FU), floxuridine (5-FUdR), capecitabine; raltitrexed; methotrexate; cladribine; gemcitabine; gemcitabine hydrochloride; thioguanine; 6-thioguanine, hydroxyurea; DNA demethylating agents, such as 5-azacytidine and decitabine; edatrexate; folic acid antagonists such as pemetrexed. Capecitabine and gemcitabine can be administered e.g. in the marketed form, such as XELODA® and GEMZAR®.

xii. an apoptosis inducer; which induces the normal series of events in a cell leading to its death, e.g. to selectively induce the X-linked mammalian inhibitor of apoptosis protein XIAP, or e.g. which downregulates BCL-xL; such as ethanol, 2-[[3-(2,3-dichlorophenoxy)propyl]amino]-(9Cl); gambogic acid; embelin, which is also known as 2,5-cyclohexadiene-1,4-dione, 2,5-dihydroxy-3-undecyl-(9Cl); arsenic trioxide.

xiii. an aurora kinase inhibitor; that target, reduce or inhibit later stages of the cell cycle from the G2/M checkpoint all the way through the mitotic checkpoint and late mitosis; such as binuclein 2, which is also known as methaneimidamide, N'-[1-(3-chloro-4-fluorophenyl)-4-cyano-1H-pyrazol-5-yl]-N,N-dimethyl-(9CI) .

xiv. a Bruton's tyrosine kinase (BTK) inhibitor; that target, reduce or inhibit human and mouse B-cell development; such as tereic acid.

xv. a calcineurin inhibitor; that target, reduce or inhibit the T-cell activation pathway, such as cypermethrin, which is also known as cyclopropanecarboxylic acid, 3-(2,2-dichloroethenyl)-2,2-dimethyl-,cyano(3-phenoxyphenyl)methyl ester (9Cl); deltamethrin, which is also known as cyclopropanecarboxylic acid, 3-(2,2-dibromoethenyl)-2,2-dimethyl-(S)-cyano(3-phenoxyphenyl)methyl ester, (1R,3R)-(9Cl); fenvalerate, which is also known as benzeneacetic acid, 4-chloro-α-(1-methylethyl)-,cyano(3-phenoxyphenyl)methyl ester (9Cl); and Tyrphostin 8; but excluding ciclosporin or FK506. xvi. a CaM kinase II inhibitor; that target, reduce or inhibit CaM kinases; which constitute a family of structurally related enzymes that include phosphorylase kinase, myosin light chain kinase and CaM kinases I-IV; such as 5-isoquinolinesulfonic acid, 4-[(2S)-2-[(5

isoquinolinylsulfonyl)methylamino]-3-oxo-3-(4-phenyl-1-piperazinyl)propyl]phenyl ester (9CI); benzenesulfonamide, N-[2-[[[3-(4-chlorophenyl)-2-propenyl]methyl]amino]methyl]phenyl]-N-(2-hydroxyethyl)-4-methoxy-(9Cl).

xvii. a CD45 tyrosine phosphatase inhibitor; that target, reduce or inhibit dephosphorylation regulatory pTyr residues on Src family protein tyrosine kinases, which aid in the treatment of a variety of inflammatory and immunological disorders; such as phosphonic acid, [[2-(4-bromophenoxy)-5-nitrophenyl]hydroxymethyl]-(9Cl).

xviii. a CDC25 phosphatase inhibitor; that target, reduce or inhibit overexpressed dephosphorylate cyclin-dependent kinases in tumors; such as 1,4-naphthalenedione, 2,3-bis[(2-hydroethyl)thio]-(9Cl).

xix. a CHK kinase inhibitor; that target, reduce or inhibit overexpression of the antiapoptotic protein Bcl-2; such as debromohymenialdisin. Targets for a CHK kinase inhibitor are CHK1 and/or CHK2.

xx. a control agent to regulate genistein, olomucin and/or tyrphostins; such as daidzein, which is also known as 4H-1-benzopyran-4-one, 7-hydroxy-3-(4-hydroxyphenyl)-(9Cl); Iso-Olomoucine, and Tyrphostin 1. xxi. a cyclooxygenase inhibitor; like for example. includes Cox-2 inhibitors; which target, reduce or inhibit the enzyme cox-2 (cyclooxygenase-2); such as 1H-indole-3-acetamide, 1-(4-chlorobenzoyl)-5-methoxy-2-methyl-N-(2-phenylethyl)-(9Cl); 5-alkyl substituted 2-arylaminophenylacetic acid and derivatives, e.g. celecoxib (CELEBREX®), rofecoxib (VIOXX®), etoricoxib, valdecoxib; or a 5-alkyl-2-arylaminophenylacetic acid, e.g. 5-methyl-2-

chloro-6'-fluoroanilino)phenylacetic acid, lumiracoxib; and celecoxib. xxii. a cRAF kinase inhibitor; that target, reduce or inhibit the upregulation of E-selectin and vascular adhesion molecule-1 induced by TNF; such as 3-(3,5-dibromo-4-hydroxybenzylidene)-5-iodo-1,3-dihydroindol-2-one; and benzamide, 3-(dimethylamino)-N-[3-[(4-hydroxybenzoyl)amino]-4-methylphenyl]-(9Cl). Raf kinases play an important role as extracellular signal-regulating kinases in cell differentiation, proliferation and apoptosis. A target for a cRAF kinase inhibitor includes, but is not limited to, RAF1.

xxiii. a cyclin-dependent kinase inhibitor; that target, reduce or inhibit cyclin-dependent kinase that plays a role in the regulation of the mammalian cell cycle; such as N9-isopropyl-olomoucine; olomoucine; purvalanol B, which is also known as benzoic acid, 2-chloro-4-[[2-[[(1R)-1-(hydroxymethyl)-2methylpropyl]amino]-9-(1-methylethyl)-9H-purine-6 -yl]amino]-(9CI); roascovitine; indirubin, which is also known as 2H-indol-2-one, 3-(1,3-dihydro-3-oxo-2H-indol-2-ylidene)-1,3-dihydro-(9CI); kenpaullone, which is also known as indolo[3,2-d][1]benzazepin-6(5H)-one, 9-bromo-7,12-dihydro-(9CI); purvalanol A, which is also known as 1-butanol, 2-[[6-[(3-chlorophenyl)amino]-9-(1-methylethyl)-9H-purin-2-yl]amino]-3-methyl- , (2R)-(9CI); indirubin-3'-monooxime. Cell cycle progression is regulated by a series of sequential events that include the activation and subsequent inactivation of cyclin-dependent kinases (Cdks) and cyclins. Cdks are a group of serine/threonine kinases that form active heterodimeric complexes by binding to their regulatory subunits, cyclins. Examples of targets of a cyclin-dependent kinase inhibitor include, but are not limited to, CDK, AHR, CDK1, CDK2, CDK5, CDK4/6, GSK3beta, and ERK.

xxiv. a cysteine protease inhibitor; that target, reduce or inhibit cysteine protease that plays a vital role in mammalian cellular turnover and apoptosis; such as 4-morpholinecarboxamide, N-[(1S)-3-fluoro-2-oxo-1-(2-phenylethyl)propyl]amino]-2-oxo-1-(phenylmethyl)ethyl]-(9Cl).

xxv. a DNA intercalator; which binds to DNA and inhibits DNA, RNA and protein synthesis; such as plicamycin, dactinomycin.

xxvi. a DNA strand breaker; which causes DNA strand cutting and results in inhibition of DNA synthesis, inhibition of RNA and protein synthesis; such as bleomycin.

xxvii. an E3 ligase inhibitor; that target, reduce or inhibit the E3 ligase that inhibits the transfer of ubiquitin chains to proteins, marking them for degradation in the proteasome; such as N-((3,3,3-trifluoro-2-trifluoromethyl)propionyl)sulfanilamide.

xxviii. an endocrine hormone; which by acting mainly on the pituitary gland causes the suppression of hormones in the male sex, the net effect being a reduction of testosterone to castration levels; in women, both ovarian estrogen and androgen synthesis is inhibited; such as leuprolide; megestrol, megestrol acetate.

xxix. compounds that target, reduce or inhibit the activity of the epidermal growth factor family of receptor tyrosine kinases (EGFR, ErbB2, ErbB3, ErbB4 as homo- or heterodimers), such as compounds, proteins or antibodies that inhibit members of the EGF receptor tyrosine kinase family, e.g. EGF receptor, ErbB2, ErbB3 and ErbB4 or binds to EGF or EGF-related ligands, and are in particular those compounds, proteins or monoclonal antibodies which are generically and specifically disclosed in WO 9702266, e.g. the compound in Example 39, EP0564409, WO9903854,

EP0520722, EP0566226, EP0787722, EP0837063, US5747498,

WO9810767, WO9730034, WO9749688, WO9738983 and especially WO9630347, e.g. a compound known as CP 358774, WO9633980, e.g. a compound known as ZD 1839; and WO 9503283, e.g. a compound known as ZM105180, which e.g. includes trastuzumab (HERCEPTIN<®>), cetuximab, iressa, OSI-774, CI-1033, EKB-569, GW-2016, E1.1, E2.4, E2.5, E6.2, E6.4, E2 .11, E6.3 or E7.6.3, 7H-pyrrolo-[2,3-d]pyrimidine derivatives such as e.g. is detailed in WO03013541, erlotinib, gefitinib. Erlotinib can be administered in the form in which it is sold as, e.g. TARCEVA®, and gefitinib as IRESSA®, human monoclonal antibodies against the epidermal growth factor receptor that includes ABX-EGFR. xxx. an EGFR, PDGFR tyrosine kinase inhibitor; such as EGFR kinase inhibitors including tyrphostin 23, tyrphostin 25, tyrphostin 47, tyrphostin 51 and tyrphostin AG 825; 2-propenamide, 2-cyano-3-(3,4-dihydroxyphenyl)-N-phenyl-(2E)-(9Cl); tyrphostin Ag 1478; lavendustin A; 3-pyridineacetonitrile, α-[(3,5-dichlorophenyl)methylene]-, (αZ)-(9Cl); an example of an EGFR, PDGFR tyrosine kinase inhibitor includes eg tyrphostin 46. PDGFR tyrosine kinase inhibitor includes tyrphostin 46. Targets of an EGFR kinase inhibitor include guanylyl cyclase (GC-C) HER2, EGFR, PTK and tubulin.

xxxi. a farnesyl transferase inhibitor; that target, reduce or inhibit the Ras protein; such as α-hydroxyfarnesylphosphonic acid; butanoic acid, 2-[[(2S)-2-[[(2S,3S)-2-[[(2R)-2-amino-3-mercaptopropyl]amino]-3-methylpentyl]oxy]-1-oxo- 3-phenylpropyl]amino]-4-(methylsulfonyl)-,1-methylethyl ester, (2S)-(9cl); manumycin A; L-744,832 or DK8G557, tipifarnib (R115777), SCH66336 (lonafarnib), BMS-214662,

xxxii. a Flk-1 kinase inhibitor; that target, reduce or inhibit Flk-1 tyrosine kinase activity; such as 2-propenamide, 2-cyano-3-[4-hydroxy-3,5-bis(1-methylethyl)phenyl]-N-(3-phenylpropyl)-(2E)-(9Cl). A target for an Flk-1 kinase inhibitor includes, but is not limited to, KDR.

xxxiii. a glycogen synthase kinase-3 (GSK3) inhibitor; that target, reduce or inhibit glycogen synthase kinase-3 (GSK3); such as indirubin-3'-monooxime. Glycogen synthase kinase-3 (GSK-3; tau protein kinase I), a highly conserved, ubiquitously expressed serine/threonine protein kinase involved in the signal transduction cascades of several cellular processes, is a protein kinase that has been shown to be involved in the regulation of various areas of cellular functions, which include protein synthesis, cell proliferation, cell differentiation, microtubule assembly/disassembly and apoptosis.

xxxiv. a histone deacetylase (HDAC) inhibitor; which inhibits histone deacetylase and which possesses anti-proliferative activity; such as compounds disclosed in WO0222577, especially N-hydroxy-3-[4-[[(2-hydroxyethyl)[2-(1H-indol-3-yl)ethyl]-amino]methyl]phenyl]-2E-2- propenamide and N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)-ethyl]-amino]methyl]phenyl]-2E-2-propenamide and pharmaceutically acceptable salts of them; suberoylanilide hydroxamic acid (SAHA); [4-(2-amino-phenylcarbamoyl)-benzyl]-carbamic acid pyridin-3-yl methyl ester and derivatives thereof; butyric acid, pyroxamide, trichostatin A, oxamflatin, apicidin, depsipeptide; depudecin; trapoxin, HC toxin, which is also known as cyclo[L-alanyl-D-alanyl-(S,2S)--amino--oxooxiranoctanoyl-D-prolyl] (9CI); sodium phenylbutyrate, suberoyl bishydroxamic acid; trichostatin A, BMS-27275, pyroxamide, FR-901228, valproic acid.

xxxv. an HSP90 inhibitor; that target, reduce or inhibit the intrinsic ATPase activity of HSP90; degrades, targets, reduces or inhibits HSP90 client proteins via the ubiquitin proteosome pathway.

Compounds that target, reduce or inhibit the intrinsic ATPase activity of HSP90 are in particular compounds, proteins or antibodies that inhibit the ATPase activity of HSP90, e.g. 17-allylamino,17-demethoxygeldanamycin (17AAG), a geldanamycin derivative; other geldanamycin-related compounds; radicicol and HDAC inhibitors. Other examples of an HSP90 inhibitor include geldanamycin, 17-demethoxy-17-(2-propenylamino)-(9Cl). Potential indirect targets of an HSP90 inhibitor include FLT3, BCR-ABL, CHK1, CYP3A5*3 and/or NQ01*2. xxxvi. an I-kappa B-alpha kinase inhibitor (IKK); that target, reduce or inhibit NF-kappaB, such as 2-propenenitrile, 3-[(4-methylphenyl)sulfonyl]-(2E)-(9Cl).

xxxvii. an insulin receptor tyrosine kinase inhibitor; which modulate the activities of phosphatidylinositol 3-kinase, microtubule-associated protein and S6 kinases; such as hydroxyl-2-naphthalenylmethylphosphonic acid, LY294002.

xxxviii. a c-Jun N-terminal kinase (JNK) kinase inhibitor; that target, reduce or inhibit Jun N-terminal kinase; such as pyrazolanthrone and/or epigallocatechin gallate. Jun N-terminal kinase (JNK), a serine-directed protein kinase, is involved in the phosphorylation and activation of c-Jun and ATF2 and plays a significant role in metabolism, growth, cell differentiation and apoptosis. A target of a JNK kinase inhibitor includes, but is not limited to, DNMT.

xxxix. a microtubule binding agent; which act by destroying the microtubule network essential for mitotic and interphase cellular function; such as vinblastine, vinblastine sulfate; vinca alkaloids, such as vincristine, vincristine sulfate; vindesin; vinorelbine; taxanes, such as docetaxel; paclitaxel; discodermolides; cochicine, epothilones and their derivatives, e.g. epothilone B or a derivative thereof. Paclitaxel is sold as TAXOL®; docetaxel as TAXOTERE®; vinblastine sulfate such as VINBLASTIN R.P®; and vincristine sulfate such as FARMISTIN®. Also included are the generic forms of paclitaxel as well as different dosage forms of paclitaxel. Generic forms of paclitaxel include, but are not limited to, betaxolol hydrochloride. Various dosage forms of paclitaxel include, but are not limited to, albumin nanoparticle paclitaxel sold as ABRAXANE®; ONXOL®, CYTOTAX®. Discodermolide can be obtained by weight, e.g. as disclosed in US5010099. Also included are epotholin derivatives which are elaborated in

US6194181, WO98/0121, WO9825929, WO9808849, WO9943653,

WO9822461 and WO0031247. Particularly preferred is epotholin A and/or B. xl. a mitogen-activated protein (MAP) kinase inhibitor; that target, reduce, or inhibit mitogen-activated protein, such as benzenesulfonamide, N-[2-[[[3-(4-chlorophenyl)-2-propenyl]methyl]amino]methyl]phenyl]-N-(2-hydroxyethyl)- 4-Methoxy-(9Cl). The mitogen-activated protein (MAP) kinases are a group of protein serine/threonine kinases that are activated in response to a number of extracellular stimuli and control signal transduction from the cell surface to the nucleus. They regulate several physiological and pathological cellular phenomena, which include inflammation, apoptotic cell death, oncogenic transformation, tumor cell invasion and metastasis.

xli. an MDM2 inhibitor; that target, reduce or inhibit the interaction of MDM2 and the p53 tumor suppressor; such as trans-4-iodo, 4'-boranyl-chalcone. xlii. a MEK inhibitor; that target, reduce or inhibit the kinase activity of the MAP kinase MEK; such as Nexavar® (sorafenib tosylate), butanenitrile, bis[amino[2-aminophenyl)thio]methylene]-(9Cl). A target for a MEK inhibitor includes, but is not limited to, ERK. An indirect target of a MEK inhibitor includes, but is not limited to, cyclin D1.

xliii. a matrix metalloproteinase (MMP) inhibitor; that target, reduce or inhibit a class of protease enzymes that selectively catalyze the hydrolysis of polypeptide bonds that include the enzymes MMP-2 and MMP-9 that are involved in promoting the loss of tissue structure around tumors and that facilitate tumor growth, angiogenesis and metastasis such as actinonin, which also is known as butanediamide, N-4-hydroxy-N1-[(1S)-1-[[(2S)-2-(hydroxymethyl)-1-pyrrolidinyl]carbonyl]-2-methylpropyl]-2-pentyl-, ( 2R)-(9CI); epigallocatechin gallate; collagen peptide mimetic and nonpeptide mimetic inhibitors; tetracycline derivatives, e.g. hydroxamate peptide mimic inhibitor batimastat; and its orally bioavailable analogs marimastat, prinomastat, metastat, neovastat, tanomastat, TAA211, BMS-279251, BAY 12-9566, MMI270B or AAJ996. A target of an MMP inhibitor includes, but is not limited to, polypeptide deformylase. xliv. an NGFR tyrosine kinase inhibitor; that target, reduce or inhibit nerve growth factor-dependent p140<c-trk >tyrosine phosphorylation; such as tyrphostin AG 879. Targets of an NGFR tyrosine kinase inhibitor include, but are not limited to, HER2, FLK1, FAK, TrkA and/or TrkC. An indirect target inhibits expression of RAF1.

xlv. a p38 MAP kinase inhibitor, which includes a SAPK2/p38 kinase inhibitor;

that target, reduce or inhibit p38-MAPK, which is a MAPK family member, such as phenol, 4-[4-(4-fluorophenyl)-5-(4-pyridinyl)-1H-imidazol-2-yl]-(9Cl ). An example of a SAPK2/p38 kinase inhibitor includes, but is not limited to, benzamide, 3-(dimethylamino)-N-[3-[(4-hydroxybenzoyl)amino]-4-methylphenyl]-(9Cl). A MAPK family member is a serine/threonine kinase activated by phosphorylation of tyrosine and threonine residues. This kinase is phosphorylated and activated by many cellular stress and inflammatory stimuli, and is believed to be involved in the regulation of important cellular responses such as apoptosis and inflammatory reactions. xlvi. a p56 tyrosine kinase inhibitor; that targets, reduces or inhibits p56 tyrosine kinase, which is an enzyme that is a lymphoid-specific src family tyrosine kinase critical for T-cell development and activation; such as damnacanthal, which is also known as 2-anthracenecarboxaldehyde,9,10-dihydro-3-hydroxy-1methoxy-9,10-dioxo-(9Cl), Tyrphostin 46. A target for a p56 tyrosine kinase inhibitor includes, but is not limited to to, Lck. Lck is associated with the cytoplasmic domains of CD4, CD8 and the beta chain of the IL-2 receptor, and is thought to be involved in the earliest steps of TCR-directed T cell activation.

xlvii. a PDGFR tyrosine kinase inhibitor; which targets, reduces or inhibits the activity of the C-kit receptor tyrosine kinases (part of the PDGFR family), such as targeting, reducing or inhibiting the activity of the c-Kit receptor tyrosine kinase family, in particular inhibiting the c-Kit receptor. Examples of targets for a PDGFR tyrosine kinase inhibitor include, but are not limited to, PDGFR, FLT3 and/or c-KIT; such as tyrphostin AG 1296; tyrphostin 9; 1,3-butadiene-1,1,3-tricarbonitrile,2-amino-4-(1H-indol-5-yl)-(9Cl); N-phenyl-2-pyrimidinamine derivative, e.g. imatinib, IRESSA®. PDGF plays a central role in regulating cell proliferation, chemotaxis and survival in normal cells as well as in various disease states such as cancer, atherosclerosis and fibrotic disease. The PDGF family is composed of dimeric isoforms (PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC, and PDGF-DD), which exert their cellular effects by differentially binding to two receptor tyrosine kinases. PDGFR-� and PDGFR-ß have molecular masses of 170 and 180 kDa, respectively.

xlviii. a phosphatidylinositol 3-kinase inhibitor; that target, reduce or inhibit PI 3-kinase; such as wortmannin, which is also known as 3H-Furo[4,3,2-de]indeno[4,5-h]-2-benzopyran-3,6,9-trione, 11-(acetyloxy)-1, 6b,7,8,9a,10,11,11b-octahydro-1-(methoxymethyl)-9a,11b-dimethyl-, (1S,6bR,9aS,11R,11bR)-(9Cl); 8-phenyl-2-(morpholin-4-yl)-chromen-4-one; quercetin, quercetin dihydrate. PI 3-kinase activity has been shown to increase in response to a variety of hormonal and growth factor stimuli, including insulin, platelet-derived growth factor, insulin-like growth factor, epidermal growth factor, colony-stimulating factor, and hepatocyte growth factor, and has been implicated in processes related to cellular growth and transformation. An example of a target for a phosphatidylinositol 3-kinase inhibitor includes, but is not limited to, Pi3K.

xlix. a phosphatase inhibitor; that target, reduce or inhibit phosphatase; such as cantharidic acid; cantharidin; and L-leucinamide, N-[4-(2-carboxyethenyl)benzoyl]glycyl-L-α-glutamyl-(E)-(9Cl). Phosphatases remove the phosphoryl group and restore the protein to its original dephosphorylated state. Consequently, the phosphorylation-dephosphorylation cycle can be seen as a molecular "on-off" switch.

l. platinum agent; which contains platinum and which inhibits DNA synthesis by forming interstrand and interstrand cross-linking of DNA molecules; such as carboplatin; cisplatin; oxaliplatin; cisplatin; satraplatin and platinum agents such as ZD0473. Carboplatin can be administered e.g. in the form in which it is sold, e.g. CARBOPLAT®; and oxaliplatin as ELOXATIN®.

li. a protein phosphatase inhibitor, which includes a PP1 and PP2 inhibitor and a tyrosine phosphatase inhibitor; that target, reduce or inhibit protein phosphatase. Examples of a PP1 and PP2A inhibitor include cantharidic acid and/or cantharidin. Examples of a tyrosine phosphatase inhibitor include, but are not limited to, L-P-bromotetramisoxalate; 2(5H)-furanone, 4-hydroxy-5-(hydroxymethyl)-3-(1-oxohexadecyl)-, (5R)-(9Cl); and benzylphosphonic acid.

The term "a PP1 or PP2 inhibitor", as used herein, refers to a compound that targets, reduces or inhibits Ser/Thr protein phosphatases. Type I phosphatases, which include PP1, can be inhibited by two heat-stable proteins known as Hemmer-1 (I-1) and Hemmer-2 (I-2). They preferentially dephosphorylate a subunit of phosphorylase kinase. Type II phosphatases are divided into spontaneously active (PP2A), CA<2+>-dependent (PP2B) and Mg<2+>-dependent (PP2C) classes of phosphatases.

The term "tyrosine phosphatase inhibitor", as used herein, refers to a compound that targets, reduces or inhibits tyrosine phosphatase.

Protein tyrosine phosphatases (PTPs) are relative newcomers to the phosphatase family. They remove phosphate groups from phosphorylated tyrosine residues in proteins. PTPs show different structural features and play important roles in the regulation of cell proliferation, differentiation, cell adhesion and motility, and cytoskeletal function. Examples of targets for a tyrosine phosphatase inhibitor include, but are not limited to, alkaline phosphatase (ALP), heparanase, PTPase, and/or prostatic acid phosphatase.

lii. a PKC inhibitor and a PKC delta kinase inhibitor: The term "a PKC inhibitor", as used herein, refers to a compound that targets, reduces or inhibits protein kinase C as well as its isozymes. Protein kinase C (PKC), a ubiquitous, phospholipid-dependent enzyme, is involved in signal transduction associated with cell proliferation, differentiation and apoptosis. Examples of a target for a PKC inhibitor include, but are not limited to, MAPK and/or NF-kappaB. Examples of a PKC inhibitor include, but are not limited to, 1-H-pyrrolo-2,5-dione,3-[1-[3-(dimethylamino)propyl]-1H-indol-3-yl]-4- (1H-indol-3-yl)-(9Cl); bisindolylmaleimide IX; sphingosine, which is known as 4-octadecene-1,3-diol, 2-amino-, (2S,3R,4E)-(9Cl); staurosporine, which is known as 9,13-epoxy1H,9H-diindolo[1,2,3-gh:3',2',1'-lm]pyrrolo[3,4-j][1,7]benzodiazonin- 1-one, staurosporine derivatives such as those disclosed in EP0296110, e.g. midostaurin; 2,3,10,11,12,13-hexahydro-10-methoxy-9-methyl-11-(methylamino)-, (9S,10R,11R,13R)-(9CI); tyrphostin 51; and hypericin, which is also known as phenanthro[1,10,9,8-opqra]perylene-7,14-dione, 1,3,4,6,8,13-hexahydroxy-10,11-dimethyl-, stereoisomer (6CI,7CI,8CI,9CI), UCN-01, safingol, BAY 43-9006, bryostatin 1, perifosine; llmofosine; RO 318220 and RO 320432; GO 6976; Isis 3521; LY333531/LY379196. The term "a PKC delta kinase inhibitor", as used herein, refers to a compound that targets, reduces or inhibits the delta isozymes of PKC. The delta isozyme is a conventional PKC isozyme and is Ca<2+>-dependent. An example of a PKC delta kinase inhibitor includes, but is not limited to, rottlerin, which is also known as 2-propen-1-one, 1-[6-[(3-acetyl-2,4,6-trihydroxy-5 -methylphenyl)methyl]-5,7-dihydroxy-2,2-dimethyl-2H-1-benzopyran-8-yl]-3-phenyl-, (2E)-(9CI).

liii. a polyamine synthesis inhibitor; which target, reduce or inhibit polyamines spermidine; such as DMFO, which is also known as (-)-2-difluoromethylornithine; N1, N12-Diethylspermine 4HCl. The polyamines spermidine and spermine are vitally important for cell proliferation, although their exact mechanism of action is unclear. Tumor cells have an altered polyamine homeostasis which is reflected by increased activity of biosynthetic enzymes and elevated polyamine pools.

life. a proteasome inhibitor; that target, reduce or inhibit the proteasome, such as aclacinomycin A; gliotoxin; PS-341; MLN 341; bortezomib; welcome. Examples of targets of a proteasome inhibitor include, but are not limited to, O(2)(-)-generating NADPH oxidase, NF-kappaB and/or farnesyltransferase, geranyltransferase I.

lv. a PTP1B inhibitor; that target, reduce or inhibit PTP1B, a protein tyrosine kinase inhibitor; such as L-leucinamide, N-[4-(2-carboxyethenyl)benzoyl]glycyl-L-α-glutamyl-,(E)-(9Cl).

lvi. a protein tyrosine kinase inhibitor that includes an SRC family tyrosine kinase inhibitor; a Syk tyrosine kinase inhibitor; and a JAK-2 and/or JAK-3 tyrosine kinase inhibitor;

The term "a protein tyrosine kinase inhibitor", as used herein, refers to a compound that targets, reduces or inhibits protein tyrosine kinases. Protein tyrosine kinases (PTKs) play a key role in the regulation of cell proliferation, differentiation, metabolism, migration and survival.

They are classified as receptor PTKs and non-receptor PTKs. Receptor PTKs contain a single polypeptide chain with a transmembrane segment. The extracellular end of this segment contains a high-affinity ligand-binding domain, while the cytoplasmic end comprises the catalytic core and regulatory sequences. Examples of targets for a tyrosine kinase inhibitor include, but are not limited to, ERK1, ERK2, Bruton's tyrosine kinase (Btk), JAK2, ERK 1⁄2, PDGFR and/or FLT3.

Examples of indirect targets include, but are not limited to, TNFalpha, NO, PGE2, IRAK, iNOS, ICAM-1 and/or E-selectin. Examples of a tyrosine kinase inhibitor include, but are not limited to, tyrphostin AG 126; tyrphostin Ag 1288; tyrphostin Ag 1295; geldanamycin; and genistein. Non-receptor tyrosine kinases include members of the Src, Tec, JAK, Fes, Abl, FAK, Csk and Syk families. They are located in the cytoplasm as well as in the nucleus. They exhibit distinct kinase regulation, substrate phosphorylation and function. Deregulation of these kinases has also been linked to several human diseases.

The term "an SRC family tyrosine kinase inhibitor", as used herein, refers to a compound that targets, reduces or inhibits SRC.

Examples of an SRC family tyrosine kinase inhibitor include, but are not limited to, PP1, which is also known as 1H-pyrazolo[3,4-d]pyrimidin-4-amine, 1-(1,1-dimethylethyl)-3-( 1-naphthalenyl)-(9CI); and PP2, which is also known as 1H-pyrazolo[3,4-d]pyrimidin-4-amine, 3-(4-chlorophenyl)-1-(1,1-dimethylethyl)-(9CI).

The term "a Syk tyrosine kinase inhibitor", as used herein, refers to a compound that targets, reduces or inhibits Syk. Examples of targets for a Syk tyrosine kinase inhibitor include, but are not limited to, Syk, STAT3 and/or STAT5. An example of a Syk tyrosine kinase inhibitor includes, but is not limited to, piceatannol, which is also known as 1,2-benzenediol, 4-[(1E)-2-(3,5-dihydroxyphenyl)ethenyl]-(9CI).

The term "a Janus (JAK-2 and/or JAK-3) tyrosine kinase inhibitor", as used herein, refers to a compound that targets, reduces or inhibits Janus tyrosine kinase. Janus tyrosine kinase inhibitors have been shown to be antileukemic agents with antithrombotic, antiallergic and immunosuppressive properties. Targets of a JAK-2 and/or JAK-3 tyrosine kinase inhibitor include, but are not limited to, JAK2, JAK3, STAT3. An indirect target of a JAK-2 and/or JAK-3 tyrosine kinase inhibitor includes, but is not limited to, CDK2. Examples of a JAK-2 and/or JAK-3 tyrosine kinase inhibitor include, but are not limited to, tyrphostin AG 490; and 2-naphthyl vinyl ketone.

Compounds that target, reduce or inhibit the activity of c-Abl family members and their gene fusion products include e.g.

PD180970 ; AG957; or NSC 680410.

lvii. a retinoid; that target, reduce or inhibit retinoid-dependent receptors; such as isotretinoin, tretinoin.

lviii. an RNA polymerase II elongation inhibitor; that target, reduce or inhibit insulin-stimulated nuclear and cytosolic p70S6 kinase in CHO cells; targets, reduces, or inhibits RNA polymerase II transcription, which may be dependent on casein kinase II; and targets, reduces or inhibits germinal vesicle degradation in bovine oocytes; such as 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole.

lix. a serine/threonine kinase inhibitor; which inhibit serine/threonine kinases; such as 2-aminopurine, also known as 1H-purine-2-amine (9Cl). An example of a target for a serine/threonine kinase inhibitor includes, but is not limited to, double-stranded RNA-dependent protein kinase (PKR). Examples of indirect targets for a serine/threonine kinase inhibitor include, but are not limited to, MCP-1, NF-kappaB, elF2alpha, COX2, RANTES, IL8, CYP2A5, IGF-1, CYP2B1, CYP2B2, CYP2H1, ALAS-1, HIF-1, erythropoietin and/or CYP1A1.

lx. a sterol biosynthesis inhibitor; which inhibit the biosynthesis of sterols such as cholesterol; such as terbinadine. Examples of targets for a sterol biosynthesis inhibitor include, but are not limited to, squalene epoxidase, and CYP2D6.

lxi. a topoisomerase inhibitor; which includes a topoisomerase I inhibitor and a topoisomerase II inhibitor. Examples of a topoisomerase I inhibitor include, but are not limited to, topotecan, gimatecan, irinotecan, camptothecan and its analogs, 9-nitrocamptothecin and the macromolecular camptothecin conjugate PNU-166148 (compound A1 in WO9917804); 10-hydroxycamptothecin acetate salt; etoposide; idarubicin hydrochloride; irinotecan hydrochloride; teniposide; topotecan, topotecan hydrochloride; doxorubicin; epirubicin, epirubicin hydrochloride; mitoxantrone, mitoxantrone hydrochloride; daunorubicin, daunorubicin hydrochloride, dasatinib (BMS-354825). Irinotecan can be administered e.g. in the form in which it is sold as, e.g. under the trademark CAMPTOSAR®. Topotecan can

administered e.g. in the form in which it is sold as, e.g. under the trademark HYCAMTIN®. The term "topoisomerase II inhibitor", as used herein, includes, but is not limited to, the anthracyclines, such as doxorubicin, which include liposomal formulation, e.g. CAELYX®, daunorubicin, which includes liposomal formulation, e.g. DAUNOSOME®, epirubicin, idarubicin and nemorubicin; the anthraquinones mitoxantrone and losoxantrone; and the podophyllotoxins etoposide and teniposide. Etoposide is marketed as ETOPOPHOS®; teniposide as VM 26-BRISTOL®; doxorubicin such as ADRIBLASTIN® or ADRIAMYCIN®; epirubicin as FARMORUBICIN®, idarubicin as ZAVEDOS®; and mitoxantrone such as NOVANTRON®.

lxii. VEGFR tyrosine kinase inhibitor; that target, reduce and/or inhibit the known angiogenic growth factors and cytokines implicated in the modulation of normal and pathological angiogenesis. The VEGF family (VEGF-A, VEGF-B, VEGF-C, VEGF-D) and their corresponding receptor tyrosine kinases [VEGFR-1 (Flt-1), VEGFR-2 (Flk-1, KDR) and VEGFR-3 ( Flt-4)] plays a superior and indispensable role in regulating the multiple facets of the angiogenic and lymphangiogenic processes. An example of a VEGFR tyrosine kinase inhibitor includes 3-(4-dimethylaminobenzylidenyl)-2-indolinone. Compounds that target, reduce or inhibit the activity of VEGFR are in particular compounds, proteins or antibodies that inhibit the VEGF receptor tyrosine kinase, inhibit a VEGF receptor or bind to VEGF, and are in particular those compounds, proteins or monoclonal antibodies that are generically and specifically elaborated in WO9835958, e.g. 1-(4-chloroanilino)-4-(4-pyridylmethyl)phthalazine or a pharmaceutically acceptable salt thereof, e.g. the succinate, or in WO0009495, WO0027820, WO0059509, WO9811223, WO0027819 and EP0769947; e.g. those described by M. Prewett et al. in Cancer Research 59 (1999) 5209-5218, by F. Yuan et al. in Proc. Natl. Acad. Sci. USA, vol.93, pages 14765-14770, December 1996, by Z. Zhu et al. in Cancer Res. 58, 1998, 3209-3214, and by J. Mordenti et al. in Toxicologic Pathology, vol. 27, no.1, pages 14-21, 1999; in WO0037502 and WO9410202; Angiostatin, described by M.S. O'Reilly et al, Cell 79, 1994, 315-328;

Endostatin described by M.S. O'Reilly et al, Cell 88, 1997, 277-285; anthranilic acid amides; ZD4190; ZD6474; SU5416; SU6668; or anti-VEGF antibodies or anti-VEGF receptor antibodies, e.g. RhuMab (bevacizumab). Antibodies mean intact monoclonal antibodies, polyclonal antibodies, multispecific antibodies formed from at least 2 intact antibodies, and antibody fragments as long as they exhibit the desired biological activity. An example of a VEGF-R2 inhibitor includes e.g. axitinib.

lxiii. a gonadorelin agonist, such as abarelix, goserelin, goserelin acetate. lxiv. a compound that induces cell differentiation processes, such as retinoic acid, alpha-, gamma- or 8-tocopherol or alpha-, gamma- or 8-tocotrienol.

lxv. a bisphosphonate, such as include etridone, clodron, tiludron, pamidron, alendron, ibandron, risedron, and zoledronic acid.

lxvi. a heparanase inhibitor that prevents heparan sulfate degradation, e.g. PI-88.

lxvii. a biological response modifier, preferably alymphokine or interferons, e.g.

interferon alfa.

lxviii. a telomerase inhibitor, e.g. telomestatin.

lxix. controllers, such as inhibitors of catechol-O-methyltransferase, e.g. entacapone. lxx. ispinesib, pertremexed (Alimta®), sunitinib (SU11248), diethylstilbestrol (DES), BMS224818 (LEA29Y).

lxxi. somatostatin or a somatostatin analogue, such as octreotide (Sandostatin® or Sandostatin LAR®).

lxxii. growth hormone receptor antagonists, such as pegvisomant, filgrastim or pegfilgrastim, or interferon alfa.

Cancer treatment, such as endocrine tumor treatment with an mTOR inhibitor, optionally in combination with an anticancer drug, as indicated herein, may be associated with radiation therapy. Endocrine tumor treatment with an mTOR inhibitor, optionally in combination with an anticancer drug, can be a second-line treatment, e.g. after treatment with another anticancer drug.

A preferred anticancer drug as a second drug substance in endocrine tumor treatment includes, e.g., 5-fluorouracil, dacarbazine, streptozotocin, a receptor tyrosine kinase inhibitor that has a spectrum of activity that includes PDGFR, C-kit, and the VEGF receptor, e.g. SU011248, growth hormone receptor antagonists, such as pegvisomant, filgrastim or pegfilgrastim, interferon alfa or somatostatin or a somatostatin analogue, such as octreotide.

Preferably, a second drug substance is somatostatin or a somatostatin analogue, such as octreotide, sold under the trade name Sandostatin® or Sandostatin LAR®.

Anti-inflammatory and/or immunomodulatory drugs that are likely to be useful in combination with an mTOR inhibitor, e.g. likely to be useful according to the present invention include e.g.

- directors, e.g. inhibitors, of calcineurin, e.g. cyclosporine A, FK 506;

- ascomycins that have immunosuppressive properties, e.g. ABT-281, ASM981; - corticosteroids; cyclophosphamide; azathioprene; leflunomide; mizoribine;

- mycophenolic acid or salt; e.g. sodium, mycophenolate mofetil;

- 15-deoxyspergualin or an immunosuppressive homologue, analogue or derivative thereof;

- directors, e.g. inhibitors, of bcr-abl tyrosine kinase activity;

- directors, e.g. inhibitors, of c-kit receptor tyrosine kinase activity;

- directors, e.g. inhibitors, of PDGF receptor tyrosine kinase activity, e.g. Gleevec (imatinib);

- directors, e.g. inhibitors, of p38 MAP kinase activity,

- directors, e.g. inhibitors, of VEGF receptor tyrosine kinase activity,

- directors, e.g. inhibitors, of PKC activity, e.g. as explained in WO0238561 or WO0382859, e.g. the compound in Example 56 or 70;

- directors, e.g. inhibitors, of JAK3 kinase activity, e.g. N-benzyl-3,4-dihydroxybenzylidene-cyanoacetamide �-cyano-(3,4-dihydroxy)-]N-benzylcinnamamide (Tyrphostin AG 490), prodigiosin 25-C (PNU156804), [4-(4'-hydroxyphenyl) -amino-6,7-dimethoxyquinazoline] (WHI-P131), [4-(3'-bromo-4'-hydroxylphenyl)-amino-6,7-dimethoxyquinazoline] (WHI-P154), [4-(3' ,5'-dibromo-4'-hydroxyphenyl)-amino-6,7-dimethoxyquinazoline] WHI-P97, KRX-211, 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo [2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile, in free form or in a pharmaceutically acceptable salt form, e.g. monocitrate (also called CP-690,550), or a compound disclosed in WO2004052359 or WO2005066156;

- directors, e.g. agonists or modulators of S1P receptor activity, e.g. FTY720 optionally phosphorylated or an analogue thereof, e.g. 2-amino-2-[4-(3-benzyloxyphenylthio)-2-chlorophenyl]ethyl-1,3-propanediol optionally phosphorylated or 1-{4-[1- (4-cyclohexyl-3-trifluoromethyl-benzyloxyimino)-ethyl]-2-ethyl-benzyl}-azetidine-3-carboxylic acid or its pharmaceutically acceptable salts;

- immunosuppressive monoclonal antibodies, e.g. monoclonal antibodies against leukocyte receptors, e.g. Lead/BAFF receptor, MHC, CD2, CD3, CD4, CD7, CD8, CD25, CD28, CD40, CD45, CD52, CD58, CD80, CD86, IL-12 receptor, IL-17 receptor, IL-23 receptor or their ligands ;

- other immunomodulatory compounds, e.g. a recombinant binding molecule having at least part of the extracellular domain of CTLA4 or a mutant thereof, e.g. at least an extracellular portion of CTLA4 or a mutant thereof linked to a non-CTLA4 protein sequence, e.g. CTLA4Ig (eg designated ATCC 68629) or a mutant thereof, e.g. LEA29Y;

- directors, e.g. inhibitors of adhesion molecule activities, e.g. LFA-1 antagonists, ICAM-1 or -3 antagonists, VCAM-4 antagonists or VLA-4 antagonists, - controllers, e.g. antagonists of CCR9 activity,

- directors, e.g. inhibitors, of MIF activity,

- 5-aminosalicylate (5-ASA) agents, such as sulfasalazine, Azulfidine®, Asacol®, Dipentum®, Pentasa®, Rowasa®, Canasa®, Colazal®, e.g. medications containing mesalamine; e.g. mesalazine in combination with heparin;

- directors, e.g. inhibitors, of TNF-alpha activity, such as e.g. include antibodies that bind to TNF-alpha, e.g. infliximab (Remicade®), thalidomide, lenalidomide, - nitric oxide-releasing non-steroidal anti-inflammatory drugs (NSAIDs), such as e.g. include COX-inhibiting NO-donating drugs (CINOD);

- phosphodiesterase, e.g. controllers, such as inhibitors of PDE4B activity,

- directors, e.g. inhibitors, of caspase activity,

- directors, e.g. agonists, of the G protein coupled receptor GPBAR1,

- directors, e.g. inhibitors, of ceramide kinase activity,

- “multi-functional anti-inflammatory” drugs (MFAIDs), e.g. cytosolic phospholipase A2 (cPLA2) inhibitors, such as membrane-anchored phospholipase A2 inhibitors linked to glycosaminoglycans;

- antibiotics, such as penicillins, cephalosporins, erythromycins, tetracyclines, sulfonamides, such as sulfadiazine, sulfisoxazole; sulfones, such as dapsone; pleuromutilins, fluoroquinolones, e.g. metronidazole, quinolones such as ciprofloxacin; levofloxacin; probiotics and commensal bacteria, e.g. Lactobacillus, Lactobacillus reuteri;

- antiviral medicines, such as ribivirine, vidarabine, acyclovir, ganciclovir, zanamivir, oseltamivir phosphate, famciclovir, atazanavir, amantadine, didanosine, efavirenz, foscarnet, indinavir, lamivudine, nelfinavir, ritonavir, saquinavir, stavudine, valacyclovir, valganciclovir, zidovudine.

Anti-inflammatory drugs that tend to be useful in combination with an mTOR inhibitor, e.g. likely to be useful according to the present invention include e.g. non-steroidal anti-inflammatory drugs (NSAIDs) such as propionic acid derivatives (alminoprofen, benoxaprofen, bucloxinic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofen and tioxaprofen), acetic acid derivatives (indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidomethacin and zomepirac), phenamic acid derivatives (flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (diflunisal and flufenisal), oxicams (isoxicam, piroxicam, sudoxicam and tenoxican), salicylates (acetylsalicylic acid, sulfasalazine) and the pyrazolones (apazon, bezpiperylon, feprazone, mofebutazone, oxyfenbutazone, phenylbutazone); cyclooxygenase-2 (COX-2) inhibitors, such as celecoxib; inhibitors of phosphodiesterase type IV (PDE-IV); antagonists of the chemokine receptors, especially CCR-1, CCR-2 and CCR-3; cholesterol-lowering agents such as HMG-CoA reductase inhibitors (lovastatin, simvastatin and pravastatin, fluvastatin, atorvastatin and other statins), sequestrants (cholestyramine and colestipol), nicotinic acid, fenofibric acid derivatives (gemfibrozil, clofibrate, fenofibrate and benzafibrate) and probucol; anticholinergic agents such as muscarinic antagonists (ipratropium bromide); other compounds such as theophylline, sulfasalazine and aminosalicylates, e.g. 5-aminosalicylic acid and their prodrugs, antirheumatic agents.

Antiallergic drugs that tend to be useful in combination with an mTOR inhibitor, e.g. likely to be useful according to the present invention include e.g. antihistamines (H1-histamine antagonists), e.g. brompheniramine, chlorpheniramine, dexchlorpheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, trimeprazine, azatadine, cyproheptadine, antazoline, pheniramine pyrilamine, astemizole, terfenadine, loratadine, cetirizine, fexofenadine, descarboethoxyloratadine, and nonsteroidal anti-inflammatory drugs -asthmatic agents such as β2-agonists (terbutaline, metaproterenol, fenoterol, isoetharine, albuterol, bitolterol, salmeterol and pirbuterol), theophylline, cromolyn sodium, atropine, ipratropium bromide, leukotriene antagonists (zafirlukast, montelukast, pranlukast, iralukast, pobilukast, SKB-106,203 ), leukotriene biosynthesis inhibitors (zileuton, BAY-1005); bronchodilators, antiasthmatic agents (mast cell stabilizers).

In each case where citations of patent applications or scientific publications are given, the subject matter relating to the compounds is hereby incorporated into the present application by reference, e.g. likewise included are the pharmaceutically acceptable salts thereof, the corresponding racemates, diastereoisomers, enantiomers, tautomers as well as the corresponding crystal modifications of the above-explained compounds where they are present, e.g. solutions, hydrates and polymorphs, which are elaborated therein. The compounds used as active ingredients in the combinations in the invention can be made and administered as described respectively in the cited documents or in the product description. Also within the scope of this invention is the combination of more than two separate active ingredients as stated above, i.e. a pharmaceutical combination within the scope of this invention could include three active ingredients or more. Furthermore, the first agent and the co-agent are not the identical ingredient.

The structure of the drug substances identified by code numbers, generic or trade names can be taken from the Internet, the real edition of the standard compendium "The Merck Index" or from databases, e.g. Patents International, e.g. IMS World Publications, or the publications mentioned above and below. The corresponding contents thereof are hereby incorporated by reference.

The use of the mTOR inhibitors in treating endocrine tumors specified above can be demonstrated in vitro, in animal test methods as well as in the clinic, for example according to the methods hereinafter described.

A. In vitro

A.1 Antiproliferative activity in combination with other agents

A cell line, e.g. the compound A resistant A549 line (IC50 in the low nM range) versus the comparative compound A resistant KB-31 and HCT116 line (IC50 in the micromolar range) are added to 96-well plates (1500 cells/well in 100 µl medium) and is incubated for 24 hours. Then, a two-fold dilution series of each compound (an mTOR inhibitor different from compound A or a known chemotherapeutic agent) was made in separate tubes (starting at 8 x IC50 of each compound) either alone or in paired combinations, and the dilutions added to the wells.

The cells were then reincubated for 3 days. Methylene blue staining is performed on day 4 and the amount of bound dye (proportional to the number of surviving cells binding to the dye) is determined. The IC50 is then determined using the Calcusyn program, which provides a measure of the interaction, namely the so-called non-exclusive combination index (CI), where: CI ~ 1 = the interaction is nearly additive; 0.85-0.9 = slight synergism; < 0.85 = synergy. In this analysis, mTOR inhibitors, e.g. compound A, interesting antiproliferative activity in combination with another chemotherapeutic agent, e.g. as defined above, e.g. in combination with somastatin or a somastatin analogue.

B. In vitro analysis

The phosphorylation status of downstream markers S6 (the inhibitor of S6K1 activity) is used as a readout, and reflects the immediate pharmacodynamic effect of the mTOR inhibitor, e.g. in the p70S6 kinase 1 (S6K1) analysis, see e.g. WO2005064343. Carcionoid power can be determined by measuring chromogranin A which, among other things, is hypersecreted in carcionoid cells, see e.g. Davies et al, Gynecology & Obstetrics 1973; 137:637-644.

C. In vitro studies

Compound A is capable of regaining the activity of endocrine agents, such as estrogen inhibitors and/or aromatase inhibitors in cells that are otherwise resistant to endocrine agent treatment. Several studies have indicated aberrant activity of the Akt kinase as a significant mechanism by which breast cancer tumors do not respond to endocrine therapy.

D. Clinical trials

In clinical trial studies involving patients with carcinoid or small cell cancer, inhibition of S6K1 activity and a reduction of chromogranin A can be observed when either compound A is given alone or a combination of Sandostatin LAR® (30 mg daily) and compound A (5 mg daily). Response evaluation can be performed every 12 weeks. Duration of study: 6 months).

Synergistic effects of such a combination are also obtained.

Further clinical studies using compound A in an amount of 5 mg or 10 mg daily (5 to 70 mg weekly) in monotherapy, and in combination therapy together with e.g.

30 mg of Sandostatin LAR® daily is being investigated, for example.

A randomized, double-blind, placebo-controlled study of compound A in 420 patients receiving therapy with Sandostatin LAR® for advanced midgut carcinoid tumors. Patients continue baseline Sandostatin LAR® therapy and are randomized to receive compound A 10 mg/day or placebo. Primary endpoint is progression free survival (PFS). Secondary endpoints include overall survival, carcinoid-associated symptoms of flushing and diarrhea, pharmacokinetics and pharmacodynamics. For efficacy assessment progression and response are assessed per RECIST criteria. Due to the nature of neuroendocrine tumors, all patients must have triphasic CT scans or MRI. Scans are repeated every two months. Purpose: Compound A in combination with Sandostatin LAR® for the treatment of advanced progressive middle arm tumor (carcinoid tumor).

A single-arm placebo-controlled study of compound A 10 mg/day in 100 patients with measurable advanced (metastatic or unresectable) pancreatic neuroendocrine tumors (small cell tumor) after failure of cytotoxic chemotherapy as a monotherapy. Primary objective is to determine the response rate. A group of 44 patients receiving chronic treatment with Sandostatin LAR® for secretory pancreatic tumors was also treated with compound A, 10 mg per day, in addition to Sandostatin LAR®.

Claims (2)

Patent claims 1. 40-O-(2-hydroxyethyl)-rapamycin for use as a single drug substance in the treatment of a carcinoid lung tumor. 2. Pharmaceutical composition comprising 40-O-(2-hydroxyethyl)-rapamycin together with at least one pharmaceutically acceptable excipient for use in the treatment according to claim 1.